Synergistic tumor microenvironment modulation enabled by a nanozyme-boosted biomimetic macrophage-derived nanovesicle for highly efficient antitumor therapy

<b>Rationale:</b> The tumor microenvironment (TME) plays a pivotal role in cancer progression, with tumor-associated macrophages (TAMs) serving as key contributors. Immunosuppressive M2-type TAMs are associated with poor prognosis and treatment resistance, highlighting the need for strategies to reprogram these cells into pro-inflammatory M1 phenotypes. To address this, we developed a TME-reshaping nanoplatform combining the tumor-targeting capability of M1 macrophage-derived nanovesicles (M1NVs) with the immunomodulatory and catalytic properties of hollow, virus-spiky hMnO_x nanozymes. This approach aims to enhance chemotherapy delivery while simultaneously reversing immunosuppression and boosting antitumor immunity. <b>Methods:</b> We engineered a biomimetic nanoplatform by physically co-extruding M1NVs with hMnO_x nanozymes. The platform was evaluated in a malignant melanoma model characterized by M2 TAM infiltration, using the first-line chemotherapeutic agent dacarbazine (DTIC) as a model drug. The system's tumor-targeting ability, cytotoxicity, and immunomodulatory effects were assessed. Additionally, the capacity of hMnO_x nanozymes to induce immunogenic cell death (ICD) and promote antigen presentation was investigated. <b>Results:</b> The nanoplatform demonstrated precise tumor-targeted delivery of DTIC <i>via</i> M1NVs, effectively inducing tumor cell death. The combination of M1NVs and hMnO_x nanozymes successfully repolarized M2 TAMs into pro-inflammatory M1 macrophages, alleviating immunosuppression and enhancing immunotherapy efficacy. Furthermore, hMnO_x nanozymes triggered ICD and improved antigen presentation, amplifying antitumor immune responses. The fabrication process was simple and scalable, underscoring the platform's potential for clinical translation. <b>Conclusion:</b> This study presents a novel nanozyme-boosted biomimetic macrophage-derived nanovesicle system that integrates precise tumor targeting, chemotherapy delivery, and TME immunomodulation. By repolarizing TAMs and enhancing antitumor immunity, the platform offers a promising strategy to overcome treatment resistance in immunosuppressive tumors. Its scalable production and high clinical potential make it a viable candidate for future cancer therapy applications.